It is known that prolongation of the QT interval may be a marker for sudden death. Measurements of the QT interval are generally taken from a 12-lead electrocardiogram. The 12-lead electrocardiogram provides only point-in-time data, thus missing the beat-to-beat dynamicity data available from a Holter recording. Heretofore, beat-to-beat data has been averaged due primarily to constraints in computing power. Unfortunately, averaging minimizes the understanding of the beat-to-beat variability inherent in QT interval data.
Increases in the QT and QTc intervals of a 12-lead Electrocardiogram (ECG) are associated with an increased risk of cardiac dysrhythmias and sudden cardiac death. See, for example, Algra A, Tijssen J G P, Roelandt R T C, Pool J, Lubsen J: QTc Prolongation measured by standard 12-lead electrocardiography is an independent risk factor for sudden death due to cardiac arrest. Circulation 83:1888, 1991; Schwartz P J, Wolf S: QT interval prolongation as predictor of sudden death in patients with myocardial infarction. Circulation 57:1074, 1978; Sawicki P T, Dahne R, Bender R, Berger M: Prolonged QT interval as a predictor of mortality in diabetic neuropathy. Diabetologia 39:77, 1996.
While the resting 12-lead electrocardiogram may provide important spacial information regarding the status of ventricular repolarization, the use of a single 12-lead ECG measured randomly in time may disregard potentially important prognostic data regarding the dynamicity, temporal relationships, and circadian rhythms of the QT interval.
It is known that the QT and QTc intervals may undergo significant changes over both the shorter and longer term due to circadian rhythms. See, for example, Yi G, Guo X, Reardon M, Gallagher M M, Hnatkova K, Camm A J, Malik M: Circadian variation of the QT interval in patients with sudden cardiac death after myocardial infarction. Am J Cardiol 81:950, 1998.
It is known that the QT and QTc intervals may undergo significant changes over both the shorter and longer term due to autonomic control. See, for example, Cappatto R, Alboni P, Pedroni P, Gilli G, Antoniolli G: Sympathetic and vagal influences on rate-dependent changes of QT interval in healthy subjects. Am J Cardiol 68:1188, 1991; Browne K F, Zipes D P, Heger J J, Prystowsky E N: Influence of the autonomic nervous system on the Q-T interval in man. Am J Cardiol 50:1099, 1982; Kautzner J, Hartikainen J E K, Heald S, Camm A J, Malik M: The effects of reflex parasympathetic stimulation on the QT interval and QT dispersion. Am J Cardiol 80:1229, 1997.
A single 12-lead ECG taken at a given point in time may provide misleading and inaccurate cardiac risk data. Therefore, analysis of the QT interval for an entire 24-hour period may provide additional information regarding the risk of sudden death not available on the single, random 12-lead ECG.
Recently, it has become possible to measure the QT interval on 24-hour Holter (AECG) recordings. These measurements have generally been reported as averages over short time periods, typically between about 15 seconds and about five minutes. See, for example, Molnar J, Zhang F, Weiss J, Ehlert F A, Rosenthal J E: Diurnal Pattern of QTc Interval: How long is prolonged? Possible relation to circadian triggers of cardiovascular events. J Am Coil Card 27:76, 1996; Yanaga T, Maruyama T, Kumanomido A, Adachi M, Noguchi S, Taguchi J: Usefulness of automatic measurement of QT interval using Holter tape in patients with hyperthyroidism. J Am Monit 6:27, 1993.
More recently beat-to-beat QT interval measurements have been used. The use of averaged QT measurements may obscure significant short-term variations in the QT intervals. Conversely, beat-to-beat measurements retain the natural variability data that may be important for calculating a patient's risk of dysrhythmia and sudden death.
Although beat-to-beat variability of the QT interval has been described by Berger and others (see Berger R D, Kasper E K, Baughman K L, Marban E, Calkins H, Tomaselli G F: Beat-to-beat QT interval variability: Novel evidence for repolarization lability in ischemic and nonischemic dilated cardiomyopathy. Circulation 96:1557, 1997), little is known regarding normal ranges in variability and measures of the QT interval over a 24-hour period using beat-to-beat measurements.
Molnar and colleagues published a study that gives some indication of the dynamic range of the QT intervals. They reported a mean maximum QTc interval of 495 ms for normal subjects using 24-hour ambulatory monitoring. They also showed a mean intra-subject change of 95 ms. Molnar further reported six normal female subjects as having a maximum mean QTc interval measurement of more than 500 ms. These mean maximum measures were taken over a five minute period. They did not report on the number of beats with a QTc that exceeded 0.45 seconds.
Morganroth and colleagues, using a manual analysis of Holter ECG recordings, found that most normal subjects had QTc intervals of greater then 0.45 seconds at some period during the 24-hour recording. See Morganroth J, Brozovich F V, McDonald J T, Jacobs R A: Variability of the QT measurement in healthy men, with implications for selection of an abnormal QT value to predict drug toxicity and proarrhythmia. Am J Cardiol 67:774, 1991.
The use of mean QTc measurements tends to obscure the individual beats that may exceed traditional normal values for QT and QTc. While traditional measurements, such as measures of central tendency, have been used extensively to describe the relationship of QT and QTc measurements to a so-called normal value, these measurements tend to ignore temporal dynamicity inherent in cardiac function. These measurements may be important to give an overall picture of the status of the subject, however.
It has long been recognized that prolongation of the QT interval may be related to sudden death in a variety of clinical syndromes. The exact relationship, however, has been difficult to define, partly because the QT interval is a dynamic measurement and changes have been observed in both the shorter term (beat-to-beat) and in the longer term (circadian rhythm).
A consistent manual measurement of the QT interval on the resting 12-lead ECG can be imprecise and non-reproducible. Savelieva et al. showed that there was a high degree of variability when using hand-measurements of the QT interval on the 12-lead ECG. See Savelieva I, Yi G, Guo X, Hnatkova K, Malik M: Agreement and reproducibility of automatic versus manual measurement of QT interval and QT dispersion. Am J Cardiol 81:471, 1998. Applicants agree with the conclusions of Savelieva and colleagues that automated measurements offer a higher degree of consistency and reliability than manual measurements.
Traditionally, the QT interval has been measured on a resting 12-lead ECG. In general, this method involves a manual estimation of the onset of the Q-wave and determination of the end of the T-wave. Several beats are used to determine the QT interval. One advantage of measuring the QT interval on a resting 12-lead ECG is that lead placement is generally consistent and a full range of electrocardiographic frequencies may be available for measurement.
One disadvantage of measuring the QT interval on a resting 12-lead ECG is related to the short observation period. The QT interval may be subject to dynamic change on both a beat-to-beat basis and over time, particularly displaying changes in circadian rhythm and in response to alteration of autonomic function. Accordingly, a 12-lead ECG may not reflect the true state of the QT interval, but only a representation at a single point in time.
Up to now, a method to measure the beat-to-beat variation of the QT interval on 24-hour AECG tapes has been unavailable. Most previous studies have focused on average QT interval measurements over several seconds or minutes, rather than individual beat-to-beat measurements.
There have been several attempts to measure the QT interval on 24-hour AECG recordings using a variety of Holter analysis systems. The sampling rate of these Holter analyzers has varied from about 125 Hz to about 200 Hz, at both 8 bit and 12-bit resolution. In addition, these systems have used averages of both RR and QT intervals to overcome data-processing problems. These averages have ranged from about 6 seconds to about 5 minutes. The use of averages tends to obscure beat-to-beat dynamic changes in QT and QTc intervals. For example, normal subjects have some beats with increased QT and QTc measurements, and subjects with known ILQT may have many normal QT and QTc measurements.
It is an objective of the present invention, in a preferred embodiment, to enable the assessment of the QT and QTc intervals and other cardiac function intervals on a beat-to-beat basis, providing a quantitative index of the percentage of individual beats with QT and QTc intervals.
It is another objective of the present invention, in a preferred embodiment, to enable the measurement and assessment of the QT and QTc intervals and other cardiac function intervals over an extended period of time, including not only periods of time greater than about one minute but also periods of time lasting at least 24 hours and even longer, in some cases.